Phenylimidazolidine derivatives and their use

ABSTRACT

Phenylimidazolidine derivatives of the general formula I   &lt;IMAGE&gt;   in which, for example, Y denotes -CH2-CH2-CO- r denotes 0 to 3 Z denotes oxygen W denotes hydroxyl R1 denotes -NH-C(=NH)-NH2 R, R2, R3 denote hydrogen R4 denotes -CO-NHR5, where -NH-R5 represents an  alpha -amino acid radical, have useful pharmacological properties such as inhibition of platelet aggregation and osteoclast binding to the bone surfaces.

The present invention relates to phenylimidazolidine derivatives, theirpreparation and their use as inhibitors of blood platelet aggregation.

Hydantoin derivatives having platelet aggregation-inhibiting action aredescribed in EP-A 449,079, and in the unpublished German PatentApplication P 41 26 277 8. Further research has shown that the compoundsof the present invention are also potent inhibitors of blood plateletaggregation.

The present invention relates to compounds of the general formula I##STR2## in which Y denotes --(CH₂)_(m) --CO--, where m represents aninteger from 1 to 4, or ##STR3## r denotes a number from 0 to 3; Zdenotes oxygen or sulphur;

W denotes hydroxyl, (C₁ -C₂₈)-alkoxy, (C₆ -C₁₄)-aryl-(C₁ -C₈)-alkoxywhich can also be substituted in the aryl radical, optionallysubstituted (C₆ -C₁₄)-aryloxy, amino or mono- or di-(C₁-C₁₈)-alkylamino;

R¹ denotes --(CH₂)_(n) --NH--X or --(CH₂)_(p) --C(═NH)--NH--X¹, where nand p represent a number 0 to 3,

X, X¹ denote hydrogen, (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxycarbonyl, (C₁-C₆)-alkylcarbonyl, (C₁ -C₁₈)-alkylcarbonyl-oxy-(C₁ -C₆)-alkoxycarbonyl,(C₆ -C₁₄)-aryloxycarbonyl, which can also be substituted in the arylradical, (C₆ -C₁₄)-aryl(C₁ -C₆)-alkoxycarbonyl which can also besubstituted in the aryl radical, cyano, hydroxyl, (C₁ -C₆)-alkoxy oramino, and

X additionally denotes a radical of the formula II

    R'--NH--C(═N--R")                                      (II)

where

R', R" independently of one another denote hydrogen, (C₁ -C₆)-alkyl, (C₁-C₆)-alkoxycarbonyl, (C₁ -C₆)-alkylcarbonyl, (C₁-C₁₈)-alkylcarbonyl-oxy-(C₁ -C₆)-alkoxycarbonyl, (C₆-C₁₄)-aryloxycarbonyl, which can also be substituted in the arylradical, (C₆ -C₁₄)-aryl(C₁ -C₆)-alkoxycarbonyl which can also besubstituted in the aryl radical, cyano, hydroxyl, (C₁ -C₆)-alkoxy oramino;

R, R² denote hydrogen or (C₁ -C₆)-alkyl;

R³ denotes hydrogen, phenyl or substituted phenyl;

R⁴ denotes hydrogen, --COOR⁵, CO--N(CH₃)R⁵ or --CO--NH--R⁵ ;

R⁵ denotes hydrogen or (C₁ -C₂₈)-alkyl which is optionally mono- orpolysubstituted by identical or different radicals from the seriesconsisting of hydroxyl, hydroxycarbonyl, aminocarbonyl, mono or di-(C₁-C₁₈)-alkylaminocarbonyl, amino-(C₂ -C₁₄)-alkylaminocarbonyl, amino(C₁-C₃)-alkylphenyl-(C₁ -C₃)-alkylaminocarbonyl, (C₁-C₁₈)-alkylcarbonylamino-(C₁ -C₃)-alkylphenyl-(C₁-C₃)-alkylaminocarbonyl, (C₁ -C₁₈)-, alkylcarbonylamino-(C₂-C₁₄)-alkylaminocarbonyl, phenyl-(C₁ -C₈)-alkoxycarbonyl, which can alsobe substituted in the aryl radical, amino, mercapto, (C₁ -C₁₈)-alkoxy,(C₁ -C₁₈)-alkoxycarbonyl, optionally substituted (C₃ -C₈)-cycloalkyl,halogen, nitro, trifluoromethyl or a radical R⁶, where

R⁶ denotes optionally substituted (C₆ -C₁₄)-aryl, optionally substituted(C₆ -C₁₄)-aryl-(C₁ -C₈)-alkyl or a monocyclic or bicyclic 5- to12-membered heterocyclic ring which can be aromatic, partiallyhydrogenated or completely hydrogenated and which, as the heteroelement,can contain one, two or three identical or different nitrogen, oxygen orsulphur atoms, or denotes a radical R⁷, where the aryl radical and,independently thereof, the heterocyclic radical can be optionallymonosubstituted or polysubstituted by identical or different radicalsfrom the series consisting of (C₁ -C₁₈)-alkyl, (C₁ -C₁₈)-alkoxy,halogen, nitro, amino and trifluoromethyl;

R⁷ denotes --NR⁸ R⁹, --OR⁸, --SR⁸, an amino acid side chain, a naturalor unnatural amino acid residue, imino acid residue, optionally N--(C₁-C₈)-alkylated or (C₆ -C₁₄)-aryl-(C₁ -C₈)-alkylated azaamino acidresidue or dipeptide residue, which can also be substituted in the arylradical and/or in which the peptide bond can be reduced to NH--CH₂, andalso their esters and amides, where free functional groups canoptionally be substituted by hydrogen or hydroxymethyl or protected byprotective groups customary in peptide chemistry, or denotes a radical--COR^(7'), in which R^(7') is defined as R⁷ ;

R⁸ denotes hydrogen, (C₂ -C₁₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl-(C₁ -C₈)-alkyl, (C₁ -C₁₈)-alkylcarbonyl, (C₁-C₁₈)-alkoxycarbonyl, (C₆ -C₁₄)-arylcarbonyl, (C₆ -C₁₄)-aryl-(C₁-C₈)-alkylcarbonyl or (C₆ -C₁₄)-aryl-(C₁ -C₁₈)-alkoxycarbonyl, where thealkyl groups can optionally be substituted by an amino group and/orwhere the aryl radicals can be monosubstituted or polysubstituted,preferably monosubstituted by identical or different radicals from theseries consisting of (C₁ -C₈)-alkyl, (C₁ -C₈)-alkoxy, halogen, nitro,amino or trifluoromethyl, a natural or unnatural amino acid residue,imino acid residue, optionally N--(C₁ -C₈)-alkylated or (C₆-C₁₄)-aryl-(C₁ -C₈)-alkylated azaamino acid residue or a dipeptideresidue, which can also be substituted in the aryl radical and/or inwhich the peptide bond can be reduced to NH--CH₂ ; and

R⁹ denotes hydrogen, (C₁ -C₁₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl or (C₆ -C₁₄)-aryl-(C₁ -C₈)-alkyl which can also besubstituted in the aryl radical;

and their physiologically tolerable salts.

Alkyl radicals can be straight-chain or branched. Preferred alkylradicals are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl and tert-butyl. The same applies to radicals such as alkoxy,alkoxycarbonyl or aralkyl. (C₃ -C₈)-Cycloalkyl radicals are inparticular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyland cyclooctyl, which, however, can also be substituted by, for example,(C₁ -C₄)-alkyl. Examples of substituted cycloalkyl radicals are4-methylcyclohexyl and 2,3-dimethylcyclopentyl.

(C₆ -C₁₄)-Aryl groups are, for example, phenyl, naphthyl, biphenylyl orfluorenyl, phenyl and naphthyl being preferred. The same applies toradicals such as aralkyl or arylcarbonyl. Aralkyl radicals are inparticular benzyl and also 1- and 2-naphthylmethyl, which can also besubstituted. The aryl radicals, in particular phenyl radicals, can alsobe monosubstituted or polysubstituted, even if they occur assubstituents of other radicals, by identical or different radicals fromthe series consisting of (C₁ -C₈)-alkyl, (C₁ -C₈)-alkoxy, halogen,nitro, amino or trifluoromethyl. Substituted aralkyl radicals are, forexample, halobenzyl or (C₁ -C₄)-alkoxybenzyl.

If phenyl is disubstituted, the substituents can be present in the 1,2-,1,3- or 1,4-position to one another. In the case of disubstitution, the1,3- and the 1,4-positions are preferred.

Heterocycles within the meaning of the above definitions are, forexample, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyrazinyl,pyrimidinyl, indolyl, isoindazolyl, indazolyl, phthalazinyl, quinolyl,isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl or a benzo-fused,cyclopenta-, cyclohexa- or cyclohepta-fused derivative of theseradicals.

These heterocycles can be substituted on a nitrogen atom by oxides, (C₁-C₇)-alkyl, for example methyl or ethyl, phenyl or phenyl-(C₁-C₄)-alkyl, for example benzyl, and/or on one or more carbon atoms by(C₁ -C₄)-alkyl, halogen, hydroxyl, (C₁ -C₄)-alkoxy, for example methoxy,phenyl-(C₁ -C₄)-alkoxy, for example benzyloxy, or oxo and can bepartially or completely saturated.

Radicals of this type are, for example, 2- or 3-pyrrolyl,phenylpyrrolyl, for example 4- or 5-phenyl-2-pyrrolyl, 2-furyl,2-thienyl, 4-imidazolyl, methylimidazolyl, for example 1-methyl-2-, -4-or -5-imidazolyl, 1,3-thiazol-2-yl, -2-, -3- or -4-pyridyl, 2-, 3- or4-pyridyl-N-oxide, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or5-indolyl, substituted 2-indolyl, for example 1-methyl-, 5-methyl-,5-methoxy-, 5-benzyloxy-, 5-chloro-or 4,5-dimethyl-2-indolyl,1-benzyl-2- or 3-indolyl, 4,5,6,7-tetrahydro-2-indolyl,cyclohepta[b]-5-pyrrolyl, 2-, 3- or 4-quinolyl, 1-, 3- or 4-isoquinolyl,1-oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl,2-benzothienyl, 2-benzoxazolyl or benzothiazolyl. Partially hydrogenatedor completely hydrogenated heterocyclic rings are, for example,dihydropyridinyl, pyrrolidinyl, for example 2-, 3- or4-N-methylpyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl,tetrahydrothienyl, benzodioxolanyl.

Halogen represents fluorine, chlorine, bromine or iodine, in particularfluorine or chlorine.

Natural and unnatural amino acids can be present, if they are chiral, inthe D- or L-form. α-Amino acids are preferred. For example, thefollowing may be mentioned (cf. Houben-Weyl, Methoden der organischenChemie (Methods of organic chemistry), Volume XV/1 and 2, Stuttgart,1974):

Aad, Abu, γAbu, ABz, 2ABz, εAca, Ach, Acp, Adpd, Ahb, Aib, βAib, Ala,βAla, ΔAla, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze,Azi, Bai, Bph, Can, Cit, Cys, (Cys)₂, Cyta, Daad, Dab, Dadd, Dap, Dapm,Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln,hGlu, His, hIle, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr,Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, βLys,ΔLys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg,Pic, Pro, ΔPro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi,βThi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val, Tbg, Npg, Chg,Cha, Thia, 2,2-diphenylaminoacetic acid, 2(p-tolyl)-2-phenylaminoaceticacid and 2-(p-chlorophenyl)aminoacetic acid.

Amino acid side chains are understood as meaning side chains of naturalor unnatural amino acids. Azaamino acids are natural or unnatural aminoacids, the central component --CHR-- or --CH₂ -- being replaced by--NR-- or --NH-- respectively.

Suitable radicals of an imino acid are in particular radicals ofheterocycles from the following group:

Pyrrolidine-2-carboxylic acid; piperidine-2-carboxylic acid;tetrahydroisoquinoline-3-carboxylic acid;decahydroisoquinoline-3-carboxylic acid; octahydroindole-2-carboxylicacid; decanhydroquinoline-2-carboxylic acid;octahydrocyclopenta[b]pyrrole-2-carboxylic acid;2-aza-bicyclo-[2.2.2]octane-3-carboxylic acid;2-azabicyclo[2.2.1.]heptane-3-carboxylic acid;2-azabicyclo[3.1.0]hexane-3-carboxylic acid;2-azaspiro[4.4]nonane-3-carboxylic acid;2-azaspiro[4.5]decane-3-carboxylic acid;spiro(bicyclo[2.2.1]-heptane)-2,3-pyrrolidine-5-carboxylic acid;spiro(bicyclo[2.2.2]octane)-2,3-pyrrolidine-5-carboxylic acid;2-azatricyclo[4.3.0.1⁶,9 ]-decane-3carboxlic acid;decahydrocyclohepta[b]pyrrole-2-carboxylic acids;decahydrocycloocta[c]pyrrole-2-carboxlic acid;octahydrocyclopenta[c]pyrrole-2-carboxylic acid;octahydroisoindole-1-carboxylic acid;2,3,3a,4,6a-hexahydrocyclopenta[b]pyrrole-2-carboxylic acid;2,3,3a,4,5,7a-hexahydroindole-2-carboxylic acid;tetrahydrothiazole-4-carboxylic acid; isoxazolidine-3-carboxylic acid;pyrazolidine-3-carboxylic acid; hydroxyproline-2-carboxylic acid; whichcan all be optionally substituted (see the following formulae): ##STR4##

The heterocycles on which the abovementioned radicals are based areknown, for example, from U.S. Pat. Nos. 4,344,949; 4,374,847; 4,350,704;EP-A 29,488; EP-A 31,741; EP-A 46,953; EP-A 49,658; EP-A 50,800; EP-A51,020; EP-A 52,870; EP-A 79,022; EP-A 84,164; EP-A 89,637; EP-A 90,341;EP-A 90,362; EP-A 105,102; EP-A 109,020; EP-A 111,873; EP-A 271,865 andEP-A 344,682.

Dipeptides can contain natural or unnatural amino acids, imino acids andalso azaamino acids as components. The natural or unnatural amino acids,imino acids, azaamino acids and dipeptides can furthermore also bepresent as esters or amides, such as, for example, methyl ester, ethylamide, semicarbazide or ω-amino-(C₄ -C₈)-alkyl amide.

Functional groups of the amino acids, imino acids and dipeptides can bepresent in protected form. Suitable protective groups such as, forexample, urethane protective groups, carboxyl protective groups and sidechain protective groups are described in Hubbuch, Kontakte (Merck) 1979,No. 3, pages 14 to 23 and in Bullesbach, Kontakte (Merck) 1980, No. 1,pages 23 to 35. The following may be mentioned in particular: Aloc,Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(NO₂),Z(Hal_(n)), Bobz, Iboc, Adpoc, Mboc, Acm, tert-butyl, OBzl, ONbzl,OMbzl, Bzl, Mob, Pic, Trt.

Physiologically tolerable salts of the compounds of the general formulaI are in particular pharmaceutically utilisable or non-toxic salts.

Such salts are formed, for example, from compounds of the generalformula I which contain acidic groups, for example carboxyl, with alkalimetals alkaline earth metals, such as, for example, Na, K, Mg and Ca,and also with physiologically tolerable organic amines, such as, forexample, triethylamine and tris(2-hydroxyethyl)amine.

Compounds of the general formula I which contain basic groups, forexample an amino group or a guanidino group, form salts with organicacids, such as, for example, hydrochloric acid, sulphuric acid orphosphoric acid and with organic carboxylic or sulphonic acids, such as,for example, acetic acid, citric acid, benzoic acid, maleic acid,fumaric acid, tartaric acid and p-toluenesulphonic acid.

Preferred compounds of the general formula I are those in which

Y denotes --(CH₂)_(m) --CO--, where m represents 1 or 2, or ##STR5## rdenotes 1; z denotes oxygen or sulphur;

W denotes hydroxyl, (C₁ -C₆)-alkoxy, particularly methoxy, ethoxy or2-propoxy;

r denotes hydrogen;

R¹ denotes --NH--C(═NH)--NH₂ ; --C(═NH)--NH₂ or --CH₂ --NH₂ ormethoxycarbonyl derivatives thereof;

R² denotes hydrogen or methyl;

R³ denotes hydrogen; and

R⁴ denotes --CO--NH--R⁵, where --NH--R⁵ represents an α-amino acidresidue or the ω-amino-(C₂ -C₈)-alkyl amide thereof.

α-amino acid radicals representing --NH--R⁵ here are particularlypreferably the valine, lysine, phenylalanine or phenylglycine residues.A particularly preferred ω-(C₂ -C₈)-alkyl amide is the 4-aminobutylamide.

The compounds of the general formula I according to the invention can beprepared by fragment condensation of a compound of the general formulaIII ##STR6## with a compound of the general formula IV ##STR7## where rand the radicals R, R¹ to R⁴ and Y, Z and W are defined as indicatedabove.

The starting peptides of the formula IV are synthesised, as a rule,stepwise from the C-terminal end. For condensation of the compounds ofthe general formula III with those of the general formula IV, thecoupling methods of peptide chemistry known per se are advantageouslyused (see, for example, Houben-Weyl, Methoden der organischen Chemie(Methods of organic chemistry), Volume 15/1 and 15/2, Stuttgart, 1974).To do this, it is necessary as a rule that amino groups contained in R¹and R⁴ are protected during the condensation by reversible protectivegroups. The same applies to the carboxyl groups of the compound of thegeneral formula IV, which are preferably present as (C₁ -C₆)-alkyl,benzyl or tert-butyl esters. Protection of amino groups is unnecessaryif the amino groups to be generated are still present as nitro or cyanogroups and are only formed after coupling by hydrogenation. Aftercoupling, the protective groups present are removed in a suitablemanner. For example, NO₂ groups (guanidino protection),benzyloxycarbonyl groups and benzyl esters can be removed byhydrogenation. Protective groups of the tert-butyl type are cleaved byacid, while the 9-flourenylmethoxycarbonyl radical is removed bysecondary amines.

The starting compounds of the general formula III can be obtained asfollows:

By reaction of amino acids, N-alkylamino acids or preferably theiresters (for example methyl, ethyl, benzyl or tert-butyl esters) (forexample of a compound of the general formula V

    R.sup.2 --NH--CH--(C.sub.6 H.sub.5 --R.sup.1)--COOCH.sub.3 (V)

with an isocyanatoalkanecarboxylic acid ester, anisothiocyanatoalkanecarboxylic ester, or an isocyanate or isothiocyanateof the aminobenzoic acid, for example of the general formula VI

    Z═C═N--Y--COOCH.sub.3                              (VI)

in which R¹, R², Y and Z are defined as indicated above, urea orthiourea derivatives are obtained, for example of the general formulaVII

    CH.sub.3 OOC--Y--NH--CZ--N(R.sup.2)--CH(C.sub.6 H.sub.5 --R.sup.1)--COOH.sub.3                                    (VII)

which cyclise by heating with acid with hydrolysis of the esterfunctions to give compounds of the general formula III. During thecyclisation, guanidino groups can be blocked by protective groups, (forexample NO₂ or Mtr). Amino groups in the side chain can likewise bepresent in protected form (for example as Boc or Z derivatives) or stillas an NO₂ or cyano function which can later be reduced to the aminogroup or, in the case of the cyano group, also converted into theformamidino group.

Otherwise, hydantoins of the general formula VIII ##STR8## in which R¹⁰denotes any desired amino acid side chain and R¹¹ denotes an amide, anamino acid residue or a peptide residue, very commonly result by basictreatment of alkoxycarbonyl peptides or aralkoxycarbonyl peptides of thegeneral formula IX

    R.sup.12 --O--CO--NH--CHR.sup.10 --CO--NH--CH.sub.2 --CO--R.sup.11(IX)

in which R¹⁰ and R¹¹ are defined as indicated above and R¹² denotesbenzyl or tert-butyl (J. S. Fruton and M. Bergmann, J. Biol. Chem. 145(1942) 253-265; C. A. Dekker, S. P. Taylor, jr. and J. S. Fruton, J.Biol. Chem. 180 (1949) 155-173; M. E. Cox, H. G. Carg, J. Hollowood, J.M. Hugo, P. M. Scopes and G. T. Young, J. Chem. Soc. (1965) 6806-6813;W. Voelter and A. Altenburg, Leibigs Ann. Chem. (1983) 1641-1655; B.Schwenzer, E. Weber and G. Losse, J. Prakt. Chem. 327 (1985) 479-486).In this case, however, the N-terminal amino acid racemises and thehydantoin hydrolyses to the urea derivative

    HOCO--CHR.sup.10 --NH--CO--NH--CH.sub.2 --CO--R.sup.11

(W. Voelter and A. Altenburg, Liebigs Ann. Chem. (1983) 1641-1655).

In comparison, a mild method is cyclisation to give the hydantoins ofcompounds of the general formula X by treatment with tetrabutylammoniumfluoride in tetrahydrofuran under reflux (J. Pless, J. Org. Chem. 39(1974) 2644-2646).

A further possibility of a mild cyclisation is trimethylsilylation ofthe peptide bond between the N-terminal amino acid and the followingglycine using bistrimethylsilyltrifluoroacetamide in acetonitrile (4hours under reflux) (J. S. Davies, R. K. Merritt and R. C. Treadgold, J.Chem. Soc. Perkin Trans. I (1982) 2939-2947).

The guanylation of the amino function can be carried out using thefollowing reagents:

1. O-Methylisothiourea (S. Weiss and H. Krommer, Chemiker Zeitung 98(1974) 617-618),

2. S-Methylisothiourea (R. F. Borne, M. L. Forrester and I. W. Waters,J. Med. Chem. 20 (1977) 771-776),

3. Nitro-S-methylisothiourea (L. S. Hafner and R. E. Evans, J. Org.Chem. 24 (1959) 1157),

4. Formamidinosulphonic acid (K. Kim, Y.-T. Lin and H. S. Mosher,Tetrah. Lett. 29 (1988) 3183-3186),

5. 3,5-Dimethyl-1-pyrazolylformamidinium nitrate (F. L. Scott, D. G.O'Donovan and J. Reilly, J. Amer. Chem. Soc. 75 (1953) 4053-4054).

6. N,N'-di-tert-Butoxycarbonyl-S-methylisothiourea (R. J. Bergeron andJ. S. McManis, J. Org. Chem. 52 (1987), 1700-1703).

Formamidines can be prepared from the corresponding cyano compounds byaddition of alcohols (for example methanol or ethanol) in acidicanhydrous medium (for example dioxane, methanol or ethanol) andsubsequent treatment with ammonia in alcohols (for example isopropanol,methanol or ethanol) (G. Wagner, P. Richter and Ch. Garbe, Pharmazie 29(1974) 12-55). A further method of preparing formamidines is theaddition of H₂ S to the cyano group, followed by methylation of theresulting thioamide and subsequent reaction with ammonia (GDR Patent No.235,866).

A further method for the preparation of the compounds of the generalformula III is the reaction of compounds of the formula X ##STR9## whereR¹³ denotes hydrogen or (C₁ -C₆)-alkyl, with phosgene, thiophosgene orappropriate equivalents to give the esters of the imidazolidinederivatives, which can then be hydrolysed to the carboxylic acids(analogously to S. Goldschmidt and M. Wick, Liebigs Ann. Chem. 575(1952) 217-231, C. Tropp. Chem. Ber. 61, (1928) 1431-1439).

The compounds of the general formula I and their physiologicallytolerable salts can be administered as medicines per se, in mixtureswith one another or in the form of pharmaceutical preparations whichpermit enteral or parenteral use and which contain, as activeconstituent, an effective dose of at least one compound of the generalformula I or of a salt thereof, in addition to customarypharmaceutically innocuous excipients and additives. The preparationsnormally contain about 0.5 to 90% by weight of the therapeuticallyactive compound.

The medicines can be administered orally, for example in the form ofpills, tablets, coated tablets, sugar-coated tablets, granules, hard andsoft gelatine capsules, solutions, syrups, emulsions or suspensions, oraerosol mixtures. Administration can also be carried out, however,rectally, for example in the form of suppositories, or parenterally, forexample in the form of injection solutions, microcapsules or rods,percutaneously, for example in the form of ointments or tinctures, ornasally, for example in the form of nasal sprays.

The pharmaceutical preparations can be prepared in a manner known perse, pharmaceutically inert inorganic or organic excipients being used.For the preparation of pills, tablets, sugar-coated tablets and hardgelatine capsules, lactose, maize starch or derivatives thereof, talc,stearic acid or its salts, etc., for example, can be used. Excipientsfor soft gelatine capsules and suppositories are, for example, fats,waxes, semi-solid and liquid polyols, natural or hardened oils, etc.Suitable excipients for the preparation of solutions and syrups are, forexample, water, sucrose, invert sugar, glucose, polyols etc. Suitableexcipients for the preparation of injection solutions are water,alcohols, glycerol, polyols or vegetable oils, etc. Suitable excipientsfor microcapsules, implants or rods are, for example, copolymers ofglycolic acid and lactic acid.

Apart from the active compounds and excipients, the pharmaceuticalpreparations can additionally contain additives such as, for example,fillers, extenders, disintegrants, binders, lubricants, wetting agents,stabilisers, emulsifiers, preservatives, sweeteners, colorants,flavourings or aromatisers, thickeners, diluents, buffer substances, andalso solvents or solubilisers or agents for achieving a depot effect aswell as salts for changing the osmotic pressure, coating agents orantioxidants. They can also contain two or more compounds of the generalformula I or their pharmacologically acceptable acid addition salts andadditionally one or more other therapeutically active substances.

Other therapeutically active substances of this type are, for example,agents promoting the circulation, such as dihydroergocristine,nicergoline, buphenine, nicotinic acid and its esters, pyridylcarbinol,bencyclan, cinnarizine, naftidrofuryl, raubasine and vincamine;positively inotropic compounds, such as digoxin, acetyldigoxin,metildigoxin and lanthanoglycosides; coronary dilators, such ascarbocromen; dipyramidol, nifedipine and perhexiline; antianginalcompounds, such as isosorbide dinitrate, isosorbide mononitrate,glycerol nitrate, molsidomine and verapamil; β-blockers, such aspropranolol, oxprenolol, atenolol, metoprolol and penbutolol. Thecompounds may moreover be combined with other nootropic substances, suchas, for example, piracetam, or CNS-active substances, such as pirlindol,sulpiride, etc.

The dose can vary within wide limits and is to be adapted to theindividual conditions in each individual case. In general, in the caseof oral administration a daily dose of about 0.1 to 1 mg/kg, preferably0.3 to 0.5 mg/kg, of body weight is appropriate to achieve effectiveresults, in the case of intravenous administration the daily dose is ingeneral about 0.01 to 0.3 mg/kg, preferably 0.05 to 0.1 mg/kg, of bodyweight. The daily dose is normally divided, in particular in the case ofthe administration of relatively large amounts, into several, forexample 2, 3 or 4, part administrations. In some cases, depending onindividual behaviour, it may be necessary to deviate upwards ordownwards from the given daily dose. Pharmaceutical preparationsnormally contain 0.2 to 50 mg, preferably 0.5 to 10 mg, of activecompound of the general formula I or one of its physiologicallytolerable salts per dose.

The compounds of the formula I according to the invention have theability to inhibit cell-cell adhesion which is due to the interaction ofArg-Gly-Asp-containing proteins, such as fibronectin, fibrinogen or thevon Willebrand factor, with the so-called integrins. Integrins aretransmembrane glycoproteins, receptors for Arg-Gly-Asp-containing cellmatrix glycoproteins (E. Ruoslahti and M. D. Pierschbacher, Science 238(1987) 491-497; D. R. Phillips, I. F. Charo, L. V. Parise and L. A.Fitzgerald, Blood 71 (1988) 831-843). They additionally inhibit thebinding of other adhesive proteins, such as vitronectin, collagen andlaminin, to the corresponding receptors on the surface of various typesof cell.

The compounds of the general formula I according to the inventioninhibit platelet aggregation, the metastasis of carcinoma cells andosteoclast binding to the bone surfaces.

The compounds of the formula I according to the invention are usedacutely in risk of thrombosis and chronically in the prevention ofarteriosclerosis and thrombosis, for example in the therapy andprophylaxis of arterial vascular diseases, such as in acute myocardialinfarct, secondary prevention of myocardial infarct, reocclusionprophylaxis after lysis and dilatation (PCTA), unstable angina pectoris,transitory ischaemic attacks, strokes, coronary bypass operationincluding bypass reocclusion prophylaxis, pulmonary embolism, peripheralarterial occlusive disease, dissecting aneurysm; in the therapy ofvenous and microcirculatory vascular disorders, such as deep veinthrombosis, disseminated intravascular clotting, post-operative andpost-partum trauma, surgical or infectious shock, septicaemia or inhyperactive platelet diseases, thrombotic thrombocytopenic purpura,preeclampsia, premenstrual syndrome, dialysis or extra-corporealcirculation; a further use is during cancer operations and alsoprophylactically in cancer. Osteoporosis can also be prevented byinhibition of osteoclast binding to the bone surface.

The compounds are tested in particular for their inhibitory action inblood platelet aggregation and the adhesion of fibrinogen to bloodplatelets. Gel-filtered blood platelets from human donor blood are used,which are activated with ADP or thrombin.

The inhibition of the binding of fibrinogen to its receptor(glycoprotein IIb/IIIa) by the compounds according to the invention istested on intact, gel-filtered human platelets. The K_(i) value of theinhibition of binding of ¹²⁵ I-fibrinogen after stimulation with ADP (10μM) is given. (References: J. S. Bennett and G. Vilaire, J. Clin.Invest. 64 (1979), 1393-1401; E. Kornecki et al., J. Biol. Chem. 256(1981), 5695-5701; G. A. Marguerie et al., J. Biol. Chem. 254 (1979),5357-5363; G. A. Marguerie et al., J. Biol. Chem. 255 (1980), 154-161).

In this test, the following results are obtained for the compounds ofExamples 1 and 2 which follow:

    ______________________________________                                        Example    Ki (μM), ADP-stimulated                                         ______________________________________                                        1          0.03                                                               2          2                                                                  ______________________________________                                    

As a functional test, the inhibition of aggregation of gel-filteredhuman platelets by the compounds according to the invention is measuredafter ADP or thrombin stimulation. The IC₅₀ value of the inhibition isgiven.

(Reference: G. A. Marguerie et al., J. Biol. Chem. 254 (1979),5357-5363)

In this test, the following results are obtained for the compounds ofExamples 1 and 2 which follow:

    ______________________________________                                                  ADP-stimulated                                                                            Thrombin-stimulated                                     Example   IC.sub.50 (μM)                                                                         IC.sub.50 9 μM)                                      ______________________________________                                        1         0.2         0.07                                                    2         6           3                                                       ______________________________________                                    

EXAMPLES

The products were identified by means of mass spectra and/or NMRspectra.

Example 1

(5-(4-Guanidinophenyl)-2,4-dioxoimidazolin-3-yl)acetyl-L-aspartyl-L-phenylglycine

1a:N-(1-Methoxycarbonyl-(4-aminophenyl)methyl),N'-ethoxycarbonylmethylurea

870 mg (4 mmol) of 4-aminophenylglycine methyl ester dihydrochloride aredissolved in 10 ml of dimethylformamide. After addition of 1 ml (8 mmol)of N-ethylmorpholine, 520 mg (4 mmol) of methyl isothiocyanatoacetateare added dropwise at -20° C. The mixture is allowed to warm to roomtemperature and is stirred for 15 hours at room temperature andconcentrated, the residue is dissolved in the ethyl acetate and thesolution is extracted with a dilute potassium hydrogen sulphatesolution. After drying, the organic solution is concentrated.

Yield: 1.2 g

1b: (5-(4-Aminophenyl)-2,4-dioxoimidazolidin-3-yl)acetic acid

1.2 g (3.9 mmol) of N-(1-methoxycarbonyl-(4-aminophenylmethyl),N-ethoxycarbonylmethylurea are heated under reflux for 30 minutes in 20ml of 6N hydrochloric acid and the mixture is concentrated in vacuo.

Yield: 1.0 g (92%)

1c: (5-(4-Nitroguanidinophenyl)-2,4-dioxoimidazolidin-3-yl)acetic acid

680 mg (5 mmol) of nitro-S-methylisothiourea and 1 g (3.5 mmol) of(5-(4-aminophenyl)-2,4-dioxoimidazolidin-3-yl)acetic acid are stirred at80° C. for 7 h in 37 ml of 0.1 molar sodium hydroxide solution. Aftercooling, the mixture is extracted with methylene chloride, and theaqueous phase is subjected to clarifying filtration and acidified to pH3 with dilute hydrochloric acid. After concentration, the residue ischromatographed for purification on Sephadex LH20 using a homogeneousmixture of butanol/glacial acetic acid/water.

Yield: 460 mg

1d:(5-(4-Nitroguanidinophenyl)-2,4-dioxoimidazolidin-3-yl)-acetyl-L-aspartyl(OtBu)-L-phenylglycine-OtBu

55 mg (0.477 mmol) of N-ethylmorpholine and 108 mg (0.523 mmol) of DCCare added at 0° C. to a solution of 160 mg (0.475 mmol) of(5-4-nitroguanidinophenyl)-2,4-dioxoimidazolidin-3yl)acetic acid, 204 mg(0.475 mmol) of H-Asp(OtBu)phenylglycine-OtBu hydrochloride and 65 mg(0.48 mmol) of hydroxybenzotriazole in 10 ml of dimethylformamide. Themixture is stirred at 0° C. for 1 hour and subsequently at roomtemperature for 5 hours. The precipitated urea is filtered off withsuction, the filtrate is concentrated and the crude product ischromatographed on a silica gel column using ethylacetate/methanol=95:5.

Yield: 304 mg (92%)

1e:(5-(4-Guanidinophenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycine

300 mg (0.43 mmol) of(5-(4-nitroguanidinophenyl)-2,4-dioxoimidazolidin-3-yl)-acetyl-L-aspartyl-L-aspartyl(OtBu)-L-phenylglycine-OtBuare allowed to stand at room temperature for 3 hours in 10 ml of 95 percent trifluoroacetic acid with occasional shaking and the mixture isconcentrated. The residue is dissolved in 50 ml of methanol and, afteraddition of 50 mg of 10% Pd on carbon, hydrogenated at room temperaturefor 5 h. The catalyst is filtered off, the filtrate is concentrated andthe residue is chromatographed for purification on Sephadex LH20 using ahomogeneous mixture of butanol/glacial acetic acid/water.

Yield: 137 mg FAB-MS 540 (M⁺ H)⁺

Example 2

(5-(3-Guanidinophenyl)-2,4-dioxoimidazolidin-3-yl)-acetyl-L-aspartyl-L-phenylglycine

This compound was prepared analogously to the method described inExample 1, starting from(5-(3-aminophenyl)-2,4-dioxoimidazolidin-3-yl)acetic acid. FAB-MS 540(M⁺ H)⁺

Example 3

(5-(4-Formamidinophenyl)-2,4-dioxoimidazolidin-3-yl)-acetyl-L-aspartyl-L-phenylglycine

Example 4

(5-(4-Aminomethylphenyl)-2,4-dioxoimidazolidin-3-yl)-acetyl-L-aspartyl-L-phenylglycine

Example 5

(5-(4-Formamidinophenyl)-4-oxo-2-thioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycine

Example 6

(5-(4-Formamidinophenyl)-4-oxo-2-thioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-lysine

Example 7

(5-(4-Formamidinophenyl)-4-oxo-2-thioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-valine

Example 8

(5-(4-Guanidinophenyl)-4-oxo-2-thioxoimidazolidin-3-yl)-acetyl-L-aspartyl-L-phenylglycine

Example 9

(5-(4-Aminomethylphenyl)-2,4-dioxoimidazolidin-3-yl)-acetyl-L-aspartyl-L-phenylalanine(4-aminobutyl)amide

Example 10

(5-(4-Methoxycarbonylguanidinophenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-(OMe)-L-phenylglycinemethyl ester

Example 11

(5-(R)-(4-Aminomethylphenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycine

a) 4-Benzyloxycarbonylaminomethyl-D-phenylglycine

1 g of 4-aminomethyl-D-phenylglycine is dissolved in 7 ml of water andtreated with 1.1 g of CuCO₃.Cu(OH)₂.0.5H₂ O. The mixture is boiled underreflux for 45 min, allowed to cool and rendered alkaline (above pH 9)using 2N sodium hydroxide solution, 0.13 ml of benzyloxycarbonylchloride is added and 2N sodium hydroxide solution is allowed to drip inwith stirring at 0° C. with pH checking. The pH should not fall below pH9. If all of the benzyloxycarbonyl chloride has reacted (no pH change),the precipitate is filtered off with suction.

Yield: 1.74 g.

The precipitate is dissolved in about 40 ml of 1N HCl at about 55° C. H₂S is passed in at 50°-60° C. until the solution has been decolourised.The CuS is filtered off and the solution is neutralised with 10 per centNH₃ solution. A precipitate is deposited, which is filtered off withsuction and washed successively with water, ethanol and ether.

Yield: 300 mg.

b) 4-Benzyloxycarbonylaminomethyl-D-phenylglycine methyl esterhydrochloride

300 mg of 4-benzyloxycarbonylaminomethyl-D-phenylglycine are suspendedin 3 ml of methanol and treated at 0° C. with 97 μl of SOCl₂. Themixture is heated with stirring at 40° C. for 4 hours. It is thenconcentrated in vacuo and the residue is triturated with ether.

Yield: 292 mg.

c)N-(1-(R)-(4-Benzyloxycarbonylaminomethylphenyl)-1-methoxycarbonylmethyl),N'-ethoxycarbonylmethylurea

290 mg of 4-benzyloxycarbonylaminomethyl-D-phenylglycine methyl esterhydrochloride are dissolved in 1.5 ml of dimethylformamide. 99 μl ofethyl isocyanatoacetate and 122 μl of triethylamine are addedsuccessively to this mixture at 0° C. The pH is adjusted to 8 using alittle triethylamine. The mixture is allowed to come to room temperatureand the dimethylformamide is removed by distillation in vacuo the nextday. The residue is partitioned between ethyl acetate and water, and theethyl acetate phase is separated off and extracted with KHSO₄ /K₂ SO₄buffer, saturated NaHCO₃ solution and water, dried over Na₂ SO₄ andconcentrated.

Yield: 310 mg.

d) (5-(R)-(4-Aminomethylphenyl)-2,4-dioxoimidazolidin-3-yl)-acetic acidhydrochloride

280 mg ofN-(1-(R)-(4-benzyloxycarbonylaminomethylphenyl-1-methoxycarbonylmethyl),N'-ethoxycarbonylmethylureaare boiled under reflux for 45 min in 4 ml of 6N HCl and the mixture isthen concentrated and dried over KOH.

Yield: 180 mg.

e)(5-(R)-(4-tert-Butoxycarbonylaminomethylphenyl)-2,4-dioxoimidazolidin-3-yl)aceticacid

A solution of 180 mg (0.6 mmol) of(5-(R)-(4-aminomethylphenyl)-2,4-dioxoimidazolidin-3-yl)acetic acidhydrochloride in a mixture of 2 ml of dioxane and 1 ml of water isadjusted to pH 8-9 at 0° C. using about 1 ml of 1N NaOH. 142 mg ofdi-tert-butyl dicarbonate are added to this mixture and it is stirred atroom temperature for 3 hours. The mixture is then concentrated in arotary evaporator and the residue is partitioned between ethyl acetateand water which has been acidified to pH 2 with KHSO₄. The ethyl acetatephase is then extracted twice by shaking with saturated NaHCO₃ solution.The combined NaHCO₃ solutions are acidified to pH 2 using KHSO₄ andextracted three times with ethyl acetate. The combined ethyl acetatephases are washed with water, dried over Na₂ SO₄ and concentrated.

Yield: 180 mg.

f)(5-(R)-(4-tert-Butoxycarbonylaminomethylphenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycinedi-tert-butyl ester

55.5 μl of N-ethylmorpholine and 97 mg of dicyclohexylcarbodiimide areadded at 0° C. to a suspension of 160 mg (0.44 mmol) of(5-(R)-(4-tert-butoxycarbonylaminomethylphenyl)-2,4-dioxoimidazolidin-3-yl)aceticacid, 183 mg of H-Asp(OtBu)-Phg-OtBu hydrochloride and 60 mg of HOBt in10 ml of dimethylformamide. The mixture is stirred at 0° C. for 1 hourand at room temperature for 3 hours. The precipitate is then filteredoff with suction and the filtrate is concentrated. The residue ispartitioned between ethyl acetate and water, and the ethyl acetate phaseis separated off and extracted with KHSO₄ /K₂ SO₄ buffer, saturatedNaHCO₃ solution and water, dried over Na₂ SO₄ and concentrated.

Yield: 340 mg.

g)(5-(R)-(4-Aminomethylphenyl)-2,4-dioxoimidazolidin-3yl)-acetyl-L-aspartyl-L-phenylglycine

310 mg of(5-(R)-(4-tert-butoxycarbonylaminomethylphenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycinedi-tert-butyl ester are dissolved in 3.1 ml of 90% strength aqueoustrifluoroacetic acid. The mixture is allowed to stand at roomtemperature for 45 min and is concentrated, and the residue ispartitioned between water and ether. The aqueous phase is freeze-dried.

Yield: 200 mg.

For purification, the substance is chromatographed in water on SephadexLH20.

Yield: 180 mg. FAB-MS: 512.2 (M+H)⁺

Example 12

(5-(4-Guanidinophenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-D-aspartyl-L-phenylglycine

FAB-MS: 540.2 (M+H)⁺

Example 13

(5-(4-Benzyloxycarbonylguanidinophenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycinediisopropyl ester

620 mg of dicyclohexylcarbodiimide are added at 0° C. to a suspension of1.2 g (2.8 mmol) of5-(4-benzyloxycarbonylguanidinophenyl)-2,4-dioxoimidazolidin-3-yl)aceticacid and 380 mg of HOBt in 180 ml of dimethylformamide and the mixtureis stirred at 0° C. for 2 hours. 1.28 g (3.3 mmol) of H-Asp-Phgdiisopropyl ester hydrochloride and 640 mg of N-ethylmorpholine are thenadded. The mixture is stirred at 0° C. for 1 hour and at roomtemperature for 3 hours. The precipitate is then filtered off withsuction and the filtrate is concentrated. The residue is partitionedbetween ethyl acetate and water, and the ethyl acetate phase isseparated off and extracted with KHSO₄ /K₂ SO₄ buffer, saturated NaHCO₃solution and water, dried over Na₂ SO₄ and concentrated.

Yield: 2.1 g. Melting point: ≈110° C. FAB-MS: 758.3 (M+H)⁺

Example 14

(5-(4-Guanidinophenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycinediisopropyl ester hydrochloride

1.0 g (1.32 mmol) of5-(4-benzyloxycarbonylguanidinophenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycinediisopropyl ester are dissolved in 200 ml of methanol and hydrogenatedat room temperature in the presence of 0.1 g of 10% Pd/C. The pH ismaintained at 4 during this reaction by dropwise addition of methanolichydrochloric acid. After the end of the hydrogenation, the catalyst isfiltered off and the filtrate is concentrated.

Yield: 850 mg FAB-MS: 624.2 (M+H)⁺

The following compounds can be prepared analogously to these Examples:

Example 15

(5-(4-Guanidinophenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycinediethyl ester hydrochloride

Melting point: ≈150° C. FAB-MS: 596.3 (M+H)⁺

Example 16

(5-(4-Di(methoxycarbonyl)guanidinophenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycinediethyl ester

Melting point: ≈100° C. FAB-MS: 712.3 (M+H)⁺

Example 17

(5-(4-Benzyloxycarbonylguanidinophenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycinediisobutyl ester

Melting point: ≈110° C. FAB-MS: 786.7 (M+H)⁺

Example 18

(5-(4-Guanidinophenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycinediisobutyl ester acetate

Melting point: >200° C. (decomp.) FAB-MS: 652.3 (M+H)⁺

Example 19

(5-(4-Benzyloxycarbonylguanidinophenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycinedimethyl ester

FAB-MS: 702.3 (M+H)⁺

Example 20

(5-(4-Guanidinophenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycinedimethyl ester hydrochloride

FAB-MS: 568.2 (M+H)⁺

Example 21

(5-(4-Benzyloxycarbonylguanidinophenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycine

FAB-MS: 674.3 (M+H)⁺

Example 22

(5-(4-Benzyloxycarbonylguanidinophenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycinemethyl ester

Melting point: ≈165° C. FAB-MS:688.5 (M+H)⁺

Example 23

(5-(4-Methoxycarbonylguanidinophenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycine

FAB-MS: 598.3 (M+H)⁺

Example 24

(5-(4-Methoxycarbonylguanidinophenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycinedimethyl ester

FAB-MS: 626.2 (M+H)⁺

Example 25

(5-(4-Methoxycarbonylguanidinophenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl(O-isopropyl)-L-phenylglycine1-hexadecyl ester

FAB-MS: 865.3 (M+H)⁺

Example 26

(5-(4-Acetylguanidinophenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycinediisopropyl ester

FAB-MS: 666.3 (M+H)⁺

Example 27

(5-(4-Aminomethylphenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycinediisopropyl ester hydrochloride

FAB-MS: 596.2 (M+H)⁺

Example 28

(5-(4-Acetylaminomethylphenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycinediisopropyl ester

FAB-MS: 638.2 (M+H)⁺

Example 29

(5-(4-Methoxycarbonylaminomethylphenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl-L-phenylglycinediisopropyl ester

FAB-MS: 654.2 (M+H)⁺

Example 30

(5-(4-Aminomethylphenyl)-2,4-dioxoimidazolidin-3-yl)acetyl-L-aspartyl(O-isopropyl)-L-phenylglycine2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl ester hydrochloride

FAB-MS: 730.3 (M+H)⁺

Examples A-H which follow relate to pharmaceutical preparations.

Example A

Emulsions containing 3 mg of active compound per 5 ml can be preparedaccording to the following recipe:

    ______________________________________                                        Active compound         0.06 g                                                Neutral oil             q.s.                                                  sodium carboxymethylcellulose                                                                         0.6 g                                                 Polyoxyethylene stearate                                                                              q.s.                                                  Pure glycerol           0.6 to 2 g                                            Flavourings             q.s.                                                  Water                   to 100 ml                                             (demineralised or distilled)                                                  ______________________________________                                    

Example B

Tablets can be prepared according to the following formulation:

    ______________________________________                                        Active compound   2 mg                                                        Lactose          60 mg                                                        Maize starch     30 mg                                                        Soluble starch    4 mg                                                        Magnesium stearate                                                                              4 mg                                                                         100 mg                                                       ______________________________________                                    

Example C

The following composition is suitable for the preparation of softgelatine capsules containing 5 mg of active compound per capsule:

    ______________________________________                                        Active compound          5 mg                                                 Mixture of triglycerides from coconut oil                                                             150 mg                                                Capsule contents        155 mg                                                ______________________________________                                    

Example D

The following formulation is suitable for the preparation ofsugar-coated tablets:

    ______________________________________                                        Active compound     3 mg                                                      Maize starch       100 mg                                                     Lactose            55 mg                                                      Sec. calcium phosphate                                                                           30 mg                                                      Soluble starch      3 mg                                                      Magnesium stearate  5 mg                                                      Colloidal silica    4 mg                                                                         200 mg                                                     ______________________________________                                    

Example E

Sugar-coated tablets containing an active compound according to theinvention and another therapeutically active substance:

    ______________________________________                                        Active compound     6 mg                                                      Propanolol         40 mg                                                      Lactose            90 mg                                                      Maize starch       90 mg                                                      Sec. calcium phosphate                                                                           34 mg                                                      Soluble starch      3 mg                                                      Magnesium stearate  3 mg                                                      Colloidal silica    4 mg                                                                         270 mg                                                     ______________________________________                                    

Example F

Sugar-coated tablets containing an active compound according to theinvention and another therapeutically active substance:

    ______________________________________                                        Active compound     5 mg                                                      Pirlindol           5 mg                                                      Lactose            60 mg                                                      Maize starch       90 mg                                                      Sec. calcium phosphate                                                                           30 mg                                                      Soluble starch      3 mg                                                      Magnesium stearate  3 mg                                                      Colloidal silica    4 mg                                                                         200 mg                                                     ______________________________________                                    

Example G

Capsules containing an active compound according to the invention andanother therapeutically active substance:

    ______________________________________                                        Active compound   5 mg                                                        Nicergoline       5 mg                                                        Maize starch     185 mg                                                                        195 mg                                                       ______________________________________                                    

Example H

Injection solutions containing 1 mg of active compound per ml can beprepared according to the following recipe:

    ______________________________________                                        Active compound          1.0 mg                                               Polyethylene glycol 400  0.3 mg                                               Sodium chloride          2.7 mg                                               Water for injection purposes to                                                                          1 ml                                               ______________________________________                                    

It is to be understood that the above described embodiments of theinvention are illustrative only, and that modifications thereof mayoccur to those skilled in the art. Accordingly, this invention is not tobe regarded as limited to the embodiments disclosed herein, but is to belimited only as defined by the appended claims.

We claim:
 1. Phenylimidazolidine derivatives of the general formula I##STR10## in which Y denotes --(CH₂)_(m) --CO--, where m represents aninteger from 1 to 4, or ##STR11## r denotes a number from 0 to 3; Zdenotes oxygen or sulphur;W denotes hydroxyl, (C₁ -C₂₈)-alkoxy, (C₆-C₁₄)-aryl-(C₁ -C₈)-alkoxy which can also be substituted in the arylradical, optionally substituted (C₆ -C₁₄)-aryloxy, amino or mono- ordi-(C₁ -C₁₈)-alkylamino; R¹ denotes --(CH₂)_(n) --NH--X or --(CH₂)_(p)--C(═NH)--NH--X¹, where n and p represent a number 0 to 3, X, X¹ denotehydrogen, (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxycarbonyl, (C₁-C₆)-alkylcarbonyl, (C₁ -C₁₈)-alkylcarbonyl-oxy-(C₁ -C₆)-alkoxycarbonyl,(C₆ -C₁₄)-aryloxycarbonyl, which can also be substituted in the arylradical, (C₆ -C₁₄)-aryl(C₁ -C₆)-alkoxycarbonyl which can also besubstituted in the aryl radical, cyano, hydroxyl, (C₁ -C₆)-alkoxy oramino, and X additionally denotes a radical of the formula II

    R'--NH--C(═N--R")                                      (II)

where R', R" independently of one another denote hydrogen, (C₁-C₆)-alkyl, (C₁ -C₆)-alkoxycarbonyl, (C₁ -C₆)-alkylcarbonyl, (C₁-C₁₈)-alkylcarbonyl-oxy-(C₁ -C₆)-alkoxycarbonyl, (C₆-C₁₄)-aryloxycarbonyl, which can also be substituted in the arylradical, (C₆ -C₁₄)-aryl(C₁ -C₆)-alkoxycarbonyl which can also besubstituted in the aryl radical, cyano, hydroxyl, (C₁ -C₆)-alkoxy oramino; alkoxycarbonyl which can also be substituted in the aryl radical,cyano, hydroxyl, (C₁ -C₆)-alkoxy or amino R, R² denote hydrogen or (C₁-C₆)-alkyl; R³ denotes hydrogen, phenyl or substituted phenyl; R⁴denotes hydrogen, --COOR⁵, CO--N(CH₃)R⁵ or --CO--NH--R⁵ ; R⁵ denoteshydrogen or (C₁ -C₂₈)-alkyl which is optionally mono- or polysubstitutedby identical or different radicals from the series consisting ofhydroxyl, hydroxycarbonyl, aminocarbonyl, mono or di-(C₁-C₁₈)-alkylaminocarbonyl, amino-(C₂ -C₁₄)-alkylaminocarbonyl, amino(C₁-C₃)-alkylphenyl-(C₁ -C₃)-alkylaminocarbonyl, (C₁-C₁₈)-alkylcarbonylamino-(C₁ -C₃)-alkylphenyl-(C₁-C₃)-alkylaminocarbonyl, (C₁ -C₁₈)-alkylcarbonylamino-(C₂-C₁₄)-alkylaminocarbonyl, phenyl-(C₁ -C₈)-alkoxycarbonyl, which can alsobe substituted in the aryl radical, amino, mercapto, (C₁ -C₁₈)-alkoxy,(C₁ -C₁₈)-alkoxycarbonyl, optionally substituted (C₃ -C₈)-cycloalkyl,halogen, nitro, trifluoromethyl or a radical R⁶, where R⁶ denotesoptionally substituted (C₆ -C₁₄)-aryl, optionally substituted (C₆-C₁₄)-aryl-(C₁ -C₈)-alkyl or a monocyclic or bicyclic 5- to 12-memberedheterocyclic ring which can be aromatic, partially hydrogenated orcompletely hydrogenated and which, as the heteroelement, can containone, two or three identical or different nitrogen, oxygen or sulphuratoms, or denotes a radical R⁷, where the aryl radical and,independently thereof, the heterocyclic radical can be optionallymonosubstituted or polysubstituted by identical or different radicalsfrom the series consisting of (C₁ -C₁₈)-alkyl, (C₁ -C₁₈)-alkoxy,halogen, nitro, amino and trifluoromethyl; R⁷ denotes --NR⁸ R⁹, --OR⁸,--SR⁸, an amino acid side chain, a natural or unnatural amino acidresidue, imino acid residue, optionally N--(C₁ -C₈)-alkylated or (C₆-C₁₄)-aryl-(C₁ -C₈)-alkylated azaamino acid residue or dipeptideresidue, which can also be substituted in the aryl radical and/or inwhich the peptide bond can be reduced to NH--CH₂, and also their estersand amides, where free functional groups can optionally be substitutedby hydrogen or hydroxymethyl or protected by protective groups customaryin peptide chemistry, or denotes a radical --COR^(7'), in which R^(7')is defined as R⁷ ; R⁸ denotes hydrogen, (C₂ -C₁₈)-alkyl, optionallysubstituted (C₆ -C₁₄)-aryl-(C₁ -C₈)-alkyl, (C₁ -C₁₈)-alkylcarbonyl, (C₁-C₁₈)-alkoxycarbonyl, (C₆ -C₁₄)-arylcarbonyl, (C₆ -C₁₄)-aryl-(C₁-C₈)-alkylcarbonyl or (C₆ -C₁₄)-aryl-(C₁ -C₁₈)-alkoxycarbonyl, where thealkyl groups can optionally be substituted by an amino group and/orwhere the aryl radicals can be monosubstituted or polysubstituted,preferably monosubstituted by identical or different radicals from theseries consisting of (C₁ -C₈)-alkyl, (C₁ -C₈)-alkoxy, halogen, nitro,amino or trifluoromethyl, a natural or unnatural amino acid residue,imino acid residue, optionally N--(C₁ -C₈)-alkylated or (C₆-C₁₄)-aryl-(C₁ -C₈)-alkylated azaamino acid residue or a dipeptideresidue, which can also be substituted in the aryl radical and/or inwhich the peptide bond can be reduced to NH--CH₂ ; and R⁹ denoteshydrogen, (C₁ -C₁₈)-alkyl, optionally substituted (C₆ -C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁ -C₈)-alkyl which can also be substituted in the arylradical;and their physiologically tolerable salts. 2.Phenylimidazolidine derivatives according to claim 1, characterised inthatY denotes --(CH₂)_(m) --CO--, where m represents 1 or 2, or##STR12## r denotes 1; z denotes oxygen or sulphur; W denotes hydroxyl,(C₁ -C₆)-alkoxy, particularly methoxy, ethoxy or 2-propoxy; R denoteshydrogen; R¹ denotes --NH--C(═NH)--NH₂ ; --C(═NH)--NH₂ or --CH₂ --NH₂ ormethoxycarbonyl derivatives thereof; R² denotes hydrogen or methyl; R³denotes hydrogen; and R⁴ denotes --CO--NH--R⁵, where --NH--R⁵ representsan α-amino acid residue or the ω-amino-(C₂ -C₈)-alkyl amide thereof. 3.Phenylimidazolidine derivatives according to claim 1, characterised inthatR⁴ denotes --CO--NH--R⁵, where --NH--R⁵ represents the valine,lysine, phenylalanine or phenylglycine residue.
 4. Phenylimidazolidinederivatives according to claim 1, characterised in that R⁴ denotes--CO--NH--R⁵, where R⁵ represents the 4-aminobutyl amide of an α-aminoacid.
 5. Process for inhibiting platelet aggregation and thromboses,comprising administering to a patient in need thereof an effective doseof a compound according to claim
 1. 6. Pharmaceutical preparation,characterised in that it contains one or more compounds of the generalformula I of claim 1 or a physiologically tolerable salt thereof asactive compound together with pharmaceutically acceptable excipients andadditives and, optionally, also one or more other pharmacological activecompounds.